According to the National Health and Nutrition Examination Survey (NHANES III, 1988 to 1994), between one third and one half of men and women in the United States are overweight. In the United States, sixty percent of men and fifty-one percent of women, of the age of 20 or older, are either overweight or obese. In addition, a large percentage of children in the United States are overweight or obese.
The cause of obesity is complex and multi-factorial. Increasing evidence suggests that obesity is not a simple problem of self-control but is a complex disorder involving appetite regulation and energy metabolism. In addition, obesity is associated with a variety of conditions associated with increased morbidity and mortality in a population. Although the etiology of obesity is not definitively established, genetic, metabolic, biochemical, cultural and psychosocial factors are believed to contribute. In general, obesity has been described as a condition in which excess body fat puts an individual at a health risk.
There is strong evidence that obesity is associated with increased morbidity and mortality. Disease risk, such as cardiovascular disease risk and type 2 diabetes disease risk, increases independently with increased body mass index. Indeed, this risk has been quantified as a five percent increase in the risk of cardiac disease for males, and a seven percent increase in the risk of cardiac disease for females, for each point of a BMI greater than 24.9 (see Kenchaiah et al., N. Engl. J. Med. 347:305, 2002; Massie, N. Engl. J. Med. 347:358, 2002). In addition, there is substantial evidence that weight loss in obese persons reduces important disease risk factors. Even a small weight loss, such as 10% of the initial body weight, in both overweight and obese adults has been associated with a decrease in risk factors such as hypertension, hyperlipidemia, and hyperglycemia.
Although diet and exercise provide a simple process to decrease weight gain, overweight and obese individuals often cannot sufficiently control these factors to effectively lose weight. Weight loss surgery is an option in carefully selected patients with clinically severe obesity. However, these treatments are high-risk, and a suitable for use in only a limited number of patients. Limited pharmacotherapy is available; several weight loss drugs have been approved by the Food and Drug Administration that can be used as part of a comprehensive weight loss program. However, there remains a need for agents that can be used to effect weight loss in overweight and obese subjects.
Under normal circumstances, animals and humans respond to starvation with a complex neuroendocrine response that ultimately leads to an increase in appetite, a relative sparing of lean body mass and burning of fat stores, and an overall decrease in basal metabolic rate (Webber & Macdonald, 1994, Brit. J. Nutr. 71:437-447; Ahima et al., 1996, Nature 382:250-252). In contrast, in some diseases a devastating pathological state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolic rate and metabolism of both fat and lean body mass, producing a relative wasting of lean body mass (Tisdale, 1997, J. Natl. Cancer Inst. 89:1763-1773; Inui, 1999, Cancer Res. 59:4493-4501; Fong et al., 1989, Amer. J. Phys. 256:R659-R665; Bruera, 1997, Brit. Med. J. 315:1219-1222; Emery, 1999, Nutrition 15:600-603). This combination is found in a number of disorders including cancer, cystic fibrosis, AIDS, rheumatoid arthritis, and renal failure (Tisdale, 1997, ibid.).
The severity of cachexia in many illnesses may be the primary determining factor in both quality of life, and in eventual mortality (Tisdale, 1997, ibid.; Larkin, 1998, Lancet 351:1336). Indeed, body mass retention in AIDS patients has a stronger correlation with survival than any other current measure of the disease (Kotler et al., 1989, Amer. J. Clin. Nutr. 50:444-447). Many different tumor types have been studied and it is a common finding that tumor-bearing animals die from cachexia and exhaustion of metabolic fuels, rather than from metastasis or infection (Svaninger et al., 1987, J. Natl. Cancer Inst. 78:943-950; Emery, 1999, Nutrition 15:600-603; Svaninger et al., 1989, Eur. J. Cancer Clin. Oncol. 25:1295-1302; Emery et al., 1984, Cancer Res. 44:2779-2784). Cachexia is commonly observed in patients with cancer, particularly in children and elderly individuals (Bruera, 1997, ibid.). The resulting malnutrition and loss of lean body mass reduces the quality of life for the affected individual and compromises recovery by decreasing tolerance to therapy and increasing post-surgical complications (Larkin, 1998, ibid.; Inui, 1999, ibid.).
Attempts at drug therapy for cachexia with a variety of agents has met with limited success (DeConno et al., 1998, Eur. J Cancer 34:1705-1709; Windisch et al., 1998, Ann. Pharmacother. 32:437-445; Rivandeneria et al., 1999, Nutr. Cancer 35:202-206; McCarthy, 1999, Res. Nurs. Health 22:380-387). The most widely utilized agent, megestrol acetate, has shown some promise in reversing weight loss, but this is primarily due to increases in fat mass and water retention, rather than preservation of lean body mass (Strang, 1997, Anticancer Res. 17:657-662). Thus, there is clearly a need to identify new agents that can be used in the treatment of cachexia and that may of use in treating other disorders, such as anorexia.